A Novel Correlation between LINE-1 Hypomethylation and the Malignancy of Gastrointestinal Stromal Tumors

Abstract

Purpose: Gastrointestinal stromal tumors (GIST) are the most important mesenchymal tumors of the gastrointestinal tract. The vast majority of GISTs exhibit activating mutations of KIT or PDGFRA, but epigenetic alteration of GISTs is largely unknown. In this study, we aimed to clarify the involvement of DNA methylation in GIST malignancy.Experimental Design: A total of 106 GIST specimens were studied. Levels of LINE-1 methylation were analyzed using bisulfite pyrosequencing. In addition, methylation of three other repetitive sequences (Alu Yb8, Satellite-α, and NBL2) was similarly analyzed, and CpG island hypermethylation was analyzed using MethyLight. Array-based comparative genomic hybridization (array CGH) was carried out in 25 GIST specimens.Results: LINE-1 hypomethylation was significantly correlated with risk, and high-risk GISTs exhibited significantly lower levels of LINE-1 methylation than low-risk (61.3% versus 53.2%; P = 0.001) or intermediate-risk GISTs (60.8% versus 53.2%; P = 0.002). Hypomethylation of Satellite-α and NBL2 was also observed in high-risk GISTs. By contrast, promoter hypermethylation was relatively infrequent (CDH1, 11.2%; MLH1, 9.8%; SFRP1, 1.2%; SFRP2, 11.0%; CHFR, 9.8%; APC, 6.1%; CDKN2A, 0%; RASSF1A, 0%; RASSF2, 0%) and did not correlate with LINE-1 methylation or risk. Array CGH analysis revealed a significant correlation between LINE-1 hypomethylation and chromosomal aberrations.Conclusions: Our data suggest that LINE-1 hypomethylation correlates significantly with the aggressiveness of GISTs and that LINE-1 methylation could be a useful marker for risk assessment. Hypomethylation may increase the malignant potential of GISTs by inducing accumulation of chromosomal aberrations. Clin Cancer Res; 16(21); 5114-23. ©2010 AACR.

Novel Clinically Relevant Genes in Gastrointestinal Stromal Tumors Identified by Exome Sequencing

“…Our data are consistent with previous reports with losses of 1p, 3p, 13q, 14q, 15q, and 22q and gains of chromosomes 4 and 5 (12)(13)(14)(15)(16)(17)(18)(19). Only one previous study of 25 GIST tumors used the same platform and provided comparable high-resolution copy number analysis (17).…”

“…Although further molecular mechanisms underlying the development and progression of GIST are not fully understood, they are necessary due to the wide range of clinical behavior. Chromosomal gains and losses resulting in altered gene dosage are known to be recurrent in GIST and believed to have a role in the molecular pathogenesis of these tumors (12)(13)(14)(15)(16)(17)(18)(19). Nevertheless, the target genes remain to be identified within these regions.…”

DNA methylation at hepatitis B viral integrants is associated with methylation at flanking human genomic sequences

“…To quantify relatively high LINE1 and AluYb8 methylation levels, we used pyrosequencing technology (Igarashi et al 2010). PCR and subsequent pyrosequencing for LINE1 and AluYb8 were performed using the PyroMark kit (Qiagen).…”

Upregulation of miR-196a andHOTAIRDrive Malignant Character in Gastrointestinal Stromal Tumors

“…In addition, we recently showed that hypomethylation of repetitive DNA elements is predominantly observed in malignant GISTs, and that global hypomethylation correlates with increased chromosomal aberration (6).…”